A woman opened an envelope that contained a white powdery substance and called authorities.
Clinton was not at the office at the time, officials said.
Police and emergency services officers were called to the Harlem office building at about 3:45 p.m., said New York Police Sgt. Reginald Watkins.
"There is a search to try to recover some sort of foreign substance," he said, adding that Secret Service agents were also at the building.
Yellow police tape blocked off the sidewalk in front of the building, but traffic was not disrupted.
Clinton spokesman Jay Carson said the building was not evacuated. He had no other details.
Secret Service spokesman Eric Zahren said a field test on the substance found it to be inert.
Mr. Clinton signed a 10-year lease for the 8,300-square foot penthouse floor of the 14-story building five years ago and started using the office in 2001. The Secret Service takes up 300 square feet of the space.
At a ceremony celebrating the new office space in 2001, Mr. Clinton said, "Now I feel like I'm home."
The city's Administration for Children's Services has a field office on four lower floors of the building.